2. Academic Validation
  3. 2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site

2-Aminothiazole Derivatives as Selective Allosteric Modulators of the Protein Kinase CK2. 1. Identification of an Allosteric Binding Site

  • J Med Chem. 2019 Feb 28;62(4):1803-1816. doi: 10.1021/acs.jmedchem.8b01766.
Benoît Bestgen 1 2 3 4 5,  Isabelle Krimm 6,  Irina Kufareva 7,  Ahmed Ashraf Moustafa Kamal 8,  Wei-Guang Seetoh 9,  Chris Abell 9,  Rolf W Hartmann 8,  Ruben Abagyan 7,  Claude Cochet 3 4 5,  Marc Le Borgne 2,  Matthias Engel 1,  Thierry Lomberget 2
Affiliations

Affiliations

  • 1 Pharmaceutical and Medicinal Chemistry , Saarland University , Campus C2.3, 66123 Saarbrücken , Germany.
  • 2 Université de Lyon, Université Lyon 1, Faculté de Pharmacie, ISPB, EA 4446 Bioactive Molecules and Medicinal Chemistry, SFR Santé Lyon-Est CNRS UMS3453, INSERM US7, F-69373 , Lyon Cedex 08, France.
  • 3 Institut National de la Santé et de la Recherche Médicale , U1036, 38000 Grenoble , France.
  • 4 Institute of Life Sciences Research and Technologies, Biology of Cancer and Infection, Commissariat à l'Energie Atomique, 38000 Grenoble , France.
  • 5 Unité Mixte de Recherche-S1036 , University of Grenoble Alpes , 38000 Grenoble , France.
  • 6 Institut des Sciences Analytiques, UMR 5280, Université de Lyon, CNRS, Université Lyon 1, ENS Lyon 5, Rue de la Doua , 69100 Villeurbanne , France.
  • 7 Skaggs School of Pharmacy and Pharmaceutical Sciences , University of California, San Diego , La Jolla , California 92093 , United States.
  • 8 Pharmaceutical and Medicinal Chemistry, Saarland University, and Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C2.3, 66123 Saarbrücken , Germany.
  • 9 Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.
PMID: 30689953 DOI: 10.1021/acs.jmedchem.8b01766
Abstract

CK2 is a ubiquitous Ser/Thr protein kinase involved in the control of various signaling pathways and is known to be constitutively active. In the present study, we identified aryl 2-aminothiazoles as a novel class of CK2 inhibitors, which displayed a non-ATP-competitive mode of action and stabilized an inactive conformation of CK2 in solution. Enzyme kinetics studies, STD NMR, circular dichroism spectroscopy, and native mass spectrometry experiments demonstrated that the compounds bind in an allosteric pocket outside the ATP-binding site. Our data, combined with molecular docking studies, strongly suggested that this new binding site was located at the interface between the αC helix and the flexible glycine-rich loop. A first hit optimization led to compound 7, exhibiting an IC50 of 3.4 μM against purified CK2α in combination with a favorable selectivity profile. Thus, we identified a novel class of CK2 inhibitors targeting an allosteric pocket, offering great potential for further optimization into Anticancer drugs.

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